This application for an Autism Center of Excellence requests five years of support for an interdisciplinary program of research on behavioral, brain and molecular aspects of the autism spectrum disorders (ASD). It builds on longstanding programmatic research focused on early mechanisms of socialization and their disruption in ASD, on their neurodevelopmental implications for brain structure and function, and on genetic and cytogenetic etiologies associated with social disorders. This application consists of 5 projects and 3 cores. Projects I, II, and III focus on the same cohort of 12- to 24-month-old infants with ASD and their outcome at 36- to 48-months of age. Their objectives include quantification of visual scanning behavior in the context of naturalistic social situations, gaze processing, and auditory preferences associated with the acquisition of language and communicative skills. A byproduct of these studies is the development of performance-based screeners for ASD in the second year of life. Project 4 uses MRI to study indices of structural and functional connectivity in a cohort of 10-year-olds who have been followed-up longitudinally since the age of 24 months through our CPEA and STAART grants. Project 5 focuses on the identification of rare genetic variants contributing to ASDs as a means of discovering molecular pathways involved in these disorders. It leverages the exceedingly well characterized cohort of infants recruited under projects I to III, builds upon our groups' recent findings implicating both cytogenetic abnormalities and sequence mutations in Contactin and Contactin associated family of molecules in developmental disorders, and capitalizes on independent results by collaborators at UCLA suggesting increased risk for ASD resulting from a common haplotype in one of these molecules. The 5 projects are integrated and supported through proven governance and communication provided by an Administrative Core. An Assessment Core will ensure well- characterized subjects in our tradition of clinical excellence and methodological rigor. A Data Analytic and Methodology Core will provide ongoing consultation on study design and data analysis, and collaborate on Center-wide data mining and methodological innovations. The Yale ACE addresses several key action items of the NIH Interagency Autism Coordinating Committee, including neuro-developmental markers and screening in infants, function-specific neural circuitry, and genetic causes.